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Targeting UDP-α-d-glucose 6-dehydrogenase inhibits glioblastoma growth and migration | Oncogene
Description:
UDP-glucose 6-dehydrogenase (UGDH) produces UDP-α-d-glucuronic acid, the precursors for glycosaminoglycans (GAGs) and proteoglycans of the extracellular matrix. Elevated GAG formation has been implicated in a variety of human diseases, including glioblastoma (GBM). In our previous study, we found that Krüppel-like factor 4 (KLF4) promotes GBM cell migration by binding to methylated DNA, mainly methylated CpGs (mCpG) and transactivating gene expression. We identified UDGH as one of the downstream targets of KLF4–mCpG binding activity. In this study, we show that KLF4 upregulates UGDH expression in a mCpG-dependent manner, and UGDH is required for KLF4-induced cell migration in vitro. UGDH knockdown decreases GAG abundance in GBM cells, as well as cell proliferation and migration in vitro. In intracranial xenografts, reduced UGDH inhibits tumor growth and migration, accompanied by a decrease in the expression of extracellular matrix proteins such as tenascin C, brevican. Our studies demonstrate a novel DNA methylation-dependent UGDH upregulation by KLF4. Developing UGDH antagonists to decrease the synthesis of extracellular matrix components will be a useful strategy for GBM therapy.
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type:PostalAddress
type:Organization
name:Jun Wan
affiliation:
name:Indiana University School of Medicine
address:
name:Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, USA
type:PostalAddress
type:Organization
name:Shuli Xia
affiliation:
name:Hugo W. Moser Research Institute at Kennedy Krieger
address:
name:Hugo W. Moser Research Institute at Kennedy Krieger, Baltimore, USA
type:PostalAddress
type:Organization
name:Johns Hopkins School of Medicine
address:
name:Department of Neurology, Johns Hopkins School of Medicine, Baltimore, USA
type:PostalAddress
type:Organization
email:[email protected]
PostalAddress:
name:Hugo W. Moser Research Institute at Kennedy Krieger, Baltimore, USA
name:Department of Pharmacology and Molecular Sciences, Johns Hopkins School of Medicine, Baltimore, USA
name:Hugo W. Moser Research Institute at Kennedy Krieger, Baltimore, USA
name:Department of Neurology, Johns Hopkins School of Medicine, Baltimore, USA
name:Department of Respiratory and Critical Care Medicine, Tongji Hospital, Tongji Medical College Huazhong University of Science and Technology, Wuhan, China
name:Hugo W. Moser Research Institute at Kennedy Krieger, Baltimore, USA
name:Department of Neurology, Johns Hopkins School of Medicine, Baltimore, USA
name:Hugo W. Moser Research Institute at Kennedy Krieger, Baltimore, USA
name:Department of Neurology, Johns Hopkins School of Medicine, Baltimore, USA
name:Department of Neurosurgery, Johns Hopkins School of Medicine, Baltimore, USA
name:Department of Oncology, Johns Hopkins School of Medicine, Baltimore, USA
name:Department of Pharmacology and Molecular Sciences, Johns Hopkins School of Medicine, Baltimore, USA
name:High throughput Biology Center, Johns Hopkins School of Medicine, Baltimore, USA
name:Department of Neurosurgery, Duke University Medical Center, Durham, USA
name:Hugo W. Moser Research Institute at Kennedy Krieger, Baltimore, USA
name:Department of Neurology, Johns Hopkins School of Medicine, Baltimore, USA
name:Hugo W. Moser Research Institute at Kennedy Krieger, Baltimore, USA
name:Department of Neurology, Johns Hopkins School of Medicine, Baltimore, USA
name:Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, USA
name:Hugo W. Moser Research Institute at Kennedy Krieger, Baltimore, USA
name:Department of Neurology, Johns Hopkins School of Medicine, Baltimore, USA
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